‘Smart’ insulin prevents diabetic highs — and deadly lows

Scientists have designed a new form of insulin that can automatically switch itself on and off depending on glucose levels in the blood. In animals, this ‘smart’ insulin1 reduced high blood-sugar concentrations effectively while preventing levels from dropping too low.
For people with diabetes, controlling blood-sugar levels is a crucial — but demanding — task. Insulin keeps blood glucose in check, helping to prevent the many long-term complications associated with high blood sugar, such as cardiovascular disease, chronic kidney disease, stroke and blindness. A large proportion of the estimated 422 million people with diabetes worldwide require insulin injections.
But excess insulin can cause blood-sugar levels to dip too low, a condition called hypoglycaemia, putting people at risk of serious complications, such as loss of consciousness, seizures and even death. Even mild or moderate hypoglycaemia can cause anxiety, weakness and confusion. People with diabetes — particularly those with type 1 diabetes, who always need to inject insulin — can have drops in blood-glucose concentrations several times a week, says Michael Weiss, a biochemist and physician at Indiana University in Indianapolis. “It really impairs quality of life.”
For decades, researchers have been working to develop a system that can automatically adjust insulin activity based on the amount of glucose in a person’s blood. One common approach has been to make a compound containing deposits that release insulin when glucose concentrations rise. But a key disadvantage of this method is its irreversibility — once insulin is released, it can’t be reined in.
The latest study, published today in Nature, gets around this issue by modifying insulin itself using glucose-sensitive components. Rita Slaaby, a principal scientist at pharmaceutical company Novo Nordisk in Bagsværd, Denmark, and her colleagues engineered an insulin molecule with a switch that turns its activity on and off in response to glucose levels in the blood. This switch consists of two parts: a ring-shaped structure known as a macrocycle and a glucoside, a molecule derived from glucose. When blood-glucose concentrations are low, the glucoside binds to the ring, keeping the insulin in a closed, inactive state. But when glucose levels in the blood rise, the sugar displaces the glucoside and changes the shape of the insulin so that it is turned on.
The researchers tested the insulin molecule, which they named NNC2215, in pigs and rats that had received infusions of glucose to mimic the effects of diabetes. They found that NNC2215 was as good as normal human insulin at lowering blood glucose when injected into the animals — and that it was able to prevent the drop in blood-glucose levels that occurred with a current insulin treatment. “This a very good study that was well designed — they did all the necessary experiments to validate that this works,” says David Sacks, a clinical chemist at the National Institutes of Health in Bethesda, Maryland. “It certainly provides encouragement that this approach is worth pursuing.”
The modified insulin is the first shown to target glucose, says Sacks. Weiss and his colleagues have previously demonstrated that an insulin molecule with a similar kind of molecular switch was sensitive to another sugar molecule, fructose2.
A few questions remain about the latest molecule. For one, the study looked at the activity of NNC2215 in a wider range of blood-glucose levels than is typically seen in people with diabetes, so future studies should demonstrate that the insulin can also be effective in a narrow range, Sacks says. Other considerations include the safety and price tag of this molecule, notes Zhen Gu, a biomedical engineer at Zhejiang University in Hangzhou, China. (Gu’s team is also designing a glucose-sensitive insulin molecule3.)
A spokesperson for Novo Nordisk says that although this study is a proof of principle of NNC2215’s glucose-sensitive insulin properties, further research to optimize the molecule is ongoing.
Several other smart insulin drugs are in the works, says Weiss, including one his own team is designing using a similar approach. Ultimately, the goal is to generate a suite of smart insulin drugs to enable doctors to individualize therapies for their patients, he adds.